The present invention relates to a procedure for oxidation of a thioether group to a sulfoxide group. More specifically, it relates to a procedure for oxidation of a thioether group in a compound with the formula (I) to a sulfoxide group, to obtain the sulfinyl derivative with the formula (II). IN said formulae (I) and (II), R2, R3, R4, R5, R6 and R8, independently from each other represent hydrogen, an alkyl group with 1 to 6 carbon atoms, or an alkoxy group with 1 to 6 carbon atoms; R7 represents hydrogen, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with 1 to 6 carbon atoms or a fluorinated alkoxy group with 1 to 6 carbon atoms; and R7 represents an alkyl group with 1 to 6 carbon atoms, a halogenated alkyl group with 1 to 6 carbon atoms, or a group such as xe2x80x94(CH2)nxe2x80x94OR9, where n is an integer between 1 and 6, both inclusive, and R9 represents hydrogen or an alkyl group with 1 to 6 carbon atoms. 
The development of procedures for synthesizing compounds with the formula (II), particularly those meant to obtain compounds with an important therapeutic activity, such as lansoprazol, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazol, omeprazol, 2-[[(3,5-dimethyl-4-methoxy-2-pyridinyl)methyl]sulfinyl]-5-methoxy-1H-benzimidazol, rabeprazol, 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazol, and pantoprazol, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazol, which are known as agents which inhibit gastric secretions and are administered to mammals for treating gastrointestinal ailments such as gastritis, gastric and duodenal ulcers, has been the object of many patents, without solving certain serious drawbacks related to these procedures.
In this sense are known in the state of the art several synthesis procedures for these 2-(2-pyridinylmethylsulfinyl) benzimidazols with the formula (II) which basically involve the synthesis of the precursor thioether and its subsequent oxidation to a sulfinyl group. Several procedures have been described for the synthesis of lansoprazol and related products such as that in patent EP-174726, which describes a procedure for oxidation of sulfur with one of m-chloroperbenzoic, peracetic, trifluoroperacetic or permalic acids, sodium bromite or sodium hypochlorite, or hydrogen peroxide.
Patent application WO98/09962 describes a method for preparing omeprazol by oxidation of its thioether precursor with a peroxyacetic acid in a biphasic medium of water and a chlorinated organic solvent. Likewise, patent application WO99/25711 also describes a method for the separation of omeprazol in which the oxidation of the thioether precursor is realized with cumenum hydroperoxide or t-butyl hydroperoxide in the presence of a titanium complex.
EP-302720 describes a procedure in which oxidation of the thioether group of compounds as 2-(2-pyridinylmethylthio) benzimidazols is achieved with hydrogen peroxide, using as catalyst vanadium pentoxide, sodium metavanadate, ammonium metavanadate or vanadium (IV) acetylacetonate.
WO98/40378 describes a procedure in which the oxidation of the thioether group of compounds as 2-(2-pyridinylmethylthio) benzimidazols is achieved by compounds of the peroxy type, such as peracids, alkylhydroperoxides, benzoylperoxides, hydrogen peroxide, metaperiodates and tetraalkylammonium perborates, etc., and as catalyst are used vanadium compounds.
Patent application WO99/02521 describes a method for oxidation of thioether to sukphoxide based on the use of a peroxoborate salt in the presence of an anhydride acid or a metal catalyst, or with an N-halosuccinimide, 1,3-dihalo-5,5-dimethylhidantoine or a salt of dichloroisocyanuric acid in the presence of a base.
Patent ES-2105953 describes the conditions for oxidation of thioether to sulfoxide based on the use of hydrogen peroxide in a medium of sodium bicarbonate, catalyzed by phosphotungstenic acid H3(P(W3O10)4)xH2O.
Patent ES-2060541 describes a procedure for oxidation of sulfur to sulfoxide with potassium peroxymonosulfate, with or without the presence of a ketone, or with hydrogen peroxide, in the presence of catalysts of Mo and V acetylacetonate.
Another patent which describes the oxidation of sulfur to sulfoxide with t-butyl hydroperoxide catalyzed by vanadium is ES-2063705, in this case for the synthesis of lansoprazol.
U.S. Pat. No. 5,374,730 describes an oxidation stage of sulfur to sulfoxide with hydrogen peroxide and catalyzed by vanadium acetylacetonate.
Patent ES-2036948 describes a procedure for the synthesis of lansoprazol, in which the last stage involves the oxidation of the thioether precursor of lansoprazol to sulfoxide, with m-chloroperbenzoic acid or magnesium monoperoxyphthalate in the presence of a quaternary ammonium salt, or hydrogen peroxide, with a W or molybdenum catalyst.
From the state of the art it is inferred that the procedure which has been developed farthest and is more widely used for oxidation is that which employs vanadium catalysts. Among these basic procedures the most efficient is the one which uses hydrogen peroxide and vanadium catalyst; and the one which uses magnesium monoperoxyphthalate (MMPP), as described in patent EP-533264. Despite this, there are unsolved drawbacks in these procedures such as the fact that vanadium compounds are relatively toxic, and that MMPP is expensive to use industrially, as well as generating phthalic acid as a reaction byproduct. Finally, in both cases sulfone and N-oxide are produced as impurities due to overoxidation. Production of these impurities obviously results in increased costs in the procedures for obtaining any of these products.
The procedure described for oxidation of the thioether precursor of lansoprazol involving the use of hydrogen peroxide and molybdenum catalysts also does not give good results as it has the drawback of producing a large amount of sulfone and some N-oxide as undesirable byproducts.
The need therefore exists to develop an improved procedure for the oxidation of these thioethers to sulfoxide, and in particular applicable to synthesis of omeprazol, lansoprazol, rabeprazol and pantoprazol, or their precursors.
The present invention relates to a procedure for oxidation of a thioether group to a sulfoxide group, and in particular for oxidation of a thioether group of a compound with the formula (I) as defined above, to a sulfinyl derivative with the formula (II).
In the sense used in this description, the term xe2x80x9chalogenated alkyl group with 1 to 6 carbon atomsxe2x80x9d signifies an alkyl group with 1 to 6 carbon atoms which contains one or more halogen atoms, preferably fluorine or chlorine, substituting one or more hydrogen atoms. Similarly, the term xe2x80x9cfluorinated alkoxy group with 1 to 6 carbon atomsxe2x80x9d signifies an alkoxy group with 1 to 6 carbon atoms which contains one or more fluorine atoms substituting one or more hydrogen atoms, such as 2,2,2-trifluoroethoxy or difluoromethoxy.
The procedure involves the oxidation of the thioether with sodium percarbonate in the presence of a molybdenum salt as a catalyst, which is preferably ammonium molybdate. This new procedure has proved to be more efficient than the various procedures described in the discussion on the state of the art. Additionally, sodium percarbonate stands out as an oxidizing agent which is easy to handle, relatively stable and simple to store.
The procedure of the present invention presents a number of improvements on the previous procedures, such as the following:
the reagents used are commercially affordable,
molybdenum catalysts are less toxic than vanadium catalysts,
the pH of the reaction mixture is slightly basic and thus adequate for stability of compounds such as lansoprazol in a solution,
the formation of N-oxide as an impurity is unappreciable or appreciable at negligible amounts,
the percentage of sulfone produced is low,
the oxidized product can be isolated by precipitation in the reaction medium,
a first purification of the sample can be performed by a fractionated precipitation at a controlled pH.
In addition, the oxidation was attempted with vanadium catalysts, but the results obtained were not satisfactory.
In a preferred realization of the procedure of the invention the oxidation is effected with a molar ratio of sodium percarbonate to the thioether with the formula (I) ranging between 0.5 and 1.4, and preferably between 0.6 and 1.2.
The amount of catalyst (molybdenum salt) employed is between 0.3% and 7%, and preferably between 0.5% and 5%, by weight, with respect to the thioether with formula (I).
The solvent used for the oxidation reaction is an alcohol with a low molecular mass, preferably methanol.
The reaction temperature is between xe2x88x9210xc2x0 C. and 25xc2x0 C., preferably between xe2x88x925xc2x0 C. and 20xc2x0 C.
Among the compounds with the formula (II) are lansoprazol, omeprazol, rabeprazol, pantoprazol and 2-[[[4-(3-hydroxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazol, which may be obtained from the corresponding thioether precursors by oxidation of the thioether group to a sulfoxide group according to the procedure provided by this invention. In a particular realization, said compounds with formula (II) are obtained by oxidation of the thioether group present in the thioether precursors with the corresponding formula (I) to sulfoxide, in methanol (solvent) with sodium percarbonate in a molar ratio with respect to the initial thioether ranging between 0.6 and 1.2, in the presence of ammonium molybdate (catalyst) with a ratio of ammonium molybdate with respect to the initial thioether between 0.5% and 5% by weight, and at a temperature between xe2x88x925xc2x0 C. and 20xc2x0 C.
2-[[[4-(3-hydroxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazol may be used as a material for the synthesis of rabeprazol by the transformation of the hydroxyl group into a methoxy group.
The following examples are provided for purposes of illustration only and should not be understood as a definition of the limits of the invention.